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Cisplatin superior to cetuximab for locally advanced head and neck cancer
NEW YORK — Cisplatin appears to be superior to cetuximab for patients with locally advanced head and neck cancer regardless of HPV status, according to a presenter at HemOnc Today New York.
However, the optimal approach for patients who truly are ineligible for cisplatin remains controversial, Joshua Bauml, MD, assistant professor of medicine in the division of hematology/oncology at Perelman School of Medicine at University of Pennsylvania, said during his presentation.
Most patients with head and neck cancer present with locally advanced disease.
Two large studies — RTOG 9501 and EORTC 22931 — established the role of cisplatin and radiation in the adjuvant setting for patients who underwent resection and had high-risk disease. Patients in these trials received cisplatin 100 mg/m2 every 3 weeks, plus radiation dosed at 60 Gy to 66 Gy over 6 to 6.5 weeks.
A combined analysis of these studies showed the addition of cisplatin was associated with improved OS among patients who had either extranodal extension or positive surgical margin.
“If you take a look at the RTOG study, though, it’s really just above the level of statistical significance,” Bauml said. “The improvement really is relatively modest, so there is large room for improvement here.”
The benefit came from improved local and regional control, as there was no difference in distant metastatic disease incidence whether chemotherapy was given or not.
“It also is important to remember that chemoradiotherapy is very toxic,” Bauml said.
Mucositis incidence is twice as high with chemoradiotherapy than with radiotherapy alone, and grade 3 to grade 4 mucositis occurs among 75% to 80% of patients with cisplatin-sensitized definitive radiotherapy.
Recovery time from mucositis can be 50% longer after chemoradiotherapy than after radiotherapy alone, and severe late toxicity is more frequent after chemoradiotherapy.
“This is a really difficult treatment to administer,” Bauml said. “This is a curable cancer and we certainly want to cure our patients, but it can be a long road for them. Based upon this toxicity, there has been some interest in decreasing the intensity of our approach.”
One such approach uses weekly cisplatin dosed at 40 mg/m2.
A randomized trial conducted in India evaluated two cisplatin regimens — weekly 30 mg/m2 vs. 100 mg/m2 every 3 weeks — plus radiotherapy as adjuvant or definitive therapy for patients with locally advanced head and neck squamous cell carcinoma.
Results published in 2017 in Journal of Clinical Oncology showed poorer local control with the weekly regimen. However, researchers observed no differences in PFS or OS.
There are key points to remember, Bauml said. Among them: 30 mg/m2 is not the preferred dose.
“A substantial number of patients only got six doses so patients were getting under our cutoff of 200 mg/m2 which we feel is the adequate minimum dose,” Bauml said.
In addition, the patient population did not represent what U.S. clinicians see in their practice, and acute toxicity was substantially worse with the every-3-week dosing.
Bauml and colleagues conducted a study using VA registry data to evaluate 2,091 patients in the VA system who received definitive chemoradiotherapy with cisplatin for HNSCC from 2000 to 2004. Researchers used propensity scores to adjust for bias by indication.
Unadjusted results showed some difference in OS, driven primarily by patients with oropharynx cancer.
“After matching for propensity score, all of that difference melted away, and we saw absolutely no difference in OS between the use of high-dose and weekly low-dose,” Bauml said. “The median dose administered in our registry was 40 mg/m2, which is more consistent with our practice. So I feel very comfortable administering weekly cisplatin based on these data.”
Notably, weekly cisplatin appeared associated with a better toxicity profile, including lower incidence of neutropenia, kidney injury, dehydration and hearing loss.
An ongoing study underway in Japan comparing these regimens in the adjuvant setting “hopefully may be a bit of a tiebreaker” between the disparate results from the study in India and the VA registry study, Bauml said.
“In the adjuvant space, if I have a patient who comes in with oral cavity cancer and they are a fit for every-3-weeks cisplatin, I think it’s important after resection to give them high-dose cisplatin, certainly those with tumors associated with Betel nut exposure,” Bauml said. “In the definitive setting, it seems weekly cisplatin may be just as active and is less toxic.”
In the RTOG 1016 study — designed to work toward treatment de-escalation — researchers randomly assigned patients with locally advanced p16-positive oropharyngeal cancer to cisplatin plus radiotherapy or cetuximab plus radiotherapy.
Cisplatin appeared associated with superior OS (P = .0163) and PFS (P = .0002).
Researchers observed no difference between groups in terms of overall rate of grade 3 or grade 4 adverse events, and no difference in mucositis incidence. Cetuximab-treated patients appeared more likely to experience acneiform rash, but cisplatin was associated with higher rates of anemia, hearing loss, nausea, vomiting, neutropenia, leukopenia, dehydration and anorexia.
Another study showed benefit with cisplatin over cetuximab for patients with p16-negative disease, with adjusted analysis showing the benefit persisted in every patient subgroup.
“I used to be a bit more laissez-faire,” Bauml said. “If I had a patient who wasn’t a great cisplatin candidate, I’d feel a bit better giving them cetuximab. Now, I will really push the envelope to try to give them cisplatin given the superior outcomes.” – by Mark Leiser
Reference:
Bauml J. Locally advanced head and neck cancer. Presented at: HemOnc Today New York; March 21-23, 2019; New York.
Disclosure: Bauml reports research/grant support from AstraZeneca, Bayer, Carevive Systems, Clovis, Janssen, Merck, Novartis and Takeda, as well as consultant services to AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Clovis, Genentech, Guardant Health, Janssen, Merck and Takeda.